Resolving Chronic Pain

The body’s own mechanism for dispersing the inflammatory reaction might lead to new treatments for chronic pain.

By Claudia Sommer and Frank Birklein | January 1, 2012

istockphoto.com, Denis Kartavenko

ISTOCKPHOTO.COM, DENIS KARTAVENKO

Inflammation is correctly blamed as one of the root causes of both acute and chronic pain—and more. Not only does chronic inflammation underlie disorders such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases, it has also been implicated in the pathogenesis of cancer, chronic heart failure, and neurological disorders such as Parkinson’s and Alzheimer’s diseases. These conditions affect millions, and carry high health-care and socioeconomic costs. And yet, inflammation is an important physiological response that jump-starts tissue repair and more carefully tunes immune reactions. Without it, we could not fight off infection or heal from injury. Why and how does this powerful ally turn into a foe?

A patient who had consulted us earlier about other problems came in complaining of swelling in her right hand, accompanied by incessant pain that left her unable to move her arm very much. An otherwise healthy 47-year-old, she had worked as a bookseller until slipping on ice and fracturing her wrist a few weeks earlier, experiencing what she described as the worst pain of her life. Surgery had been successful, but as she healed, the swelling in her wrist did not resolve. Instead, the swelling had extended to the whole hand, even increasing after her cast was removed, and the hand had become exquisitely sensitive. It appeared to be permanently swollen, reddish in color, and was usually warmer than her other hand. Because of the pain, she was unable to return to her job or perform any exercise, and needed help with many everyday tasks. X-rays did not reveal any pathology that would explain the pain. Treatment with anti-inflammatory drugs like aspirin was ineffective; even morphine provided little relief.

Her doctors finally arrived at a diagnosis of complex regional pain syndrome and she began a multicomponent pain treatment program. Treatment included very specific physical and cognitive therapies that resulted in a 90 percent restoration of hand function and a reduction in pain. Today, complex regional pain syndrome is thought to be initiated by an unusually strong and long-lasting inflammatory reaction to trauma, although its treatment is not always so successful.

Although not all cases of chronic pain involve inflammation, the majority do. Therapy options for chronic pain are complicated because of the ongoing nature of the symptom.

In chronic pain, the inflammatory factors are never completely cleared from the system.

While the causes of chronic pain are many and diverse, the pervasive effect it has on a patient’s life—including inability to work, anxiety, depression, and even post-traumatic stress disorder—is universal. Opiates such as morphine are considered among the best medications for relieving pain, but they carry a risk of tolerance and addiction, especially with long-term use. Many doctors thus prefer to prescribe anti-inflammatory drugs such as cyclooxygenase (COX) inhibitors. COX inhibitors, like aspirin or ibuprofen, however, can cause gastrointestinal bleeding and kidney damage when used at high doses, and selective COX-2 inhibitors such as Vioxx have been shown to increase the risk of cardiovascular disease. In addition, these drugs are most effective for mild and moderate pain; they have a “ceiling” beyond which taking more provides no more relief.

One difference between acute inflammation and the persistent inflammation that leads to chronic pain, is that in the latter, the inflammatory factors are never completely cleared from the system. Recent research has revealed that the clearing of these inflammatory factors is an active process rather than a passive one that simply occurs over time. This insight offers the possibility that we might be able to harness resolution factors that clear inflammation and use them to ameliorate the pain that accompanies chronic inflammation.

Reducing inflammation

In 2000, while looking for bioactive molecules derived from the metabolism of omega-3 fatty acids, Charlie Serhan’s laboratory at Brigham and Women’s Hospital at Harvard Medical School discovered a compound that naturally reduces inflammation after an acute reaction.[1. C.N. Serhan et al., “Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals,” J Exp Med, 196:1025-37, 2002.],[2. C.N. Serhan “Systems approach to inflammation resolution: identification of novel anti-inflammatory and pro-resolving mediators,” J Thromb Haemost, 7 (Suppl 1):44-48, 2009.] Omega-3 fatty acids, which can be found in foods such as fish and flaxseed oil, include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These two fatty acids have long been known to have beneficial effects in reducing the risk of several diseases, including atherosclerosis, asthma, heart disease, and cancer. The American Heart Association even recommends the consumption of fish rich in omega-3 fatty acids for cardiovascular disease prevention. However, it was not known whether omega-3 fatty acids actively reduced inflammation. The problem was confounded by the fact that many studies investigating the effects included patients who were also taking aspirin, making it difficult to tease apart the anti-inflammatory contribution of each. The Serhan laboratory set out to analyze the interaction of EPA and DHA with aspirin and to identify molecular components derived from the fatty acids.

First, they analyzed the composition of lipid-based compounds that were present in tissues during the resolution of acute inflammation in the mouse. Mice produced fatty acid metabolites that the investigators dubbed “resolvins” for their ability to reduce the inflammatory reaction. Although these compounds appeared to clear the inflammation, the process was different from active suppression of the immune system. The resolvins did not hinder immune cell action; rather, they reduced the inflammatory activity of specific populations of cells and blocked their production of pro-inflammatory chemokines, while increasing the action of immune cells that clear dead tissue.

Serhan’s team also showed that these resolving molecules were naturally derived from omega-3 fatty acids—and that aspirin enhanced this conversion. When they then administered the resolvins to animal models of acute and chronic inflammation such as peritonitis, colitis, or asthma, they saw an accelerated return to homeostasis.

The study demonstrated how aspirin could increase the production of the body’s own natural inflammation mediators by catalyzing the metabolism of the touted omega-3 fatty acids into chemical forms that diminish inflammation. In addition, it appeared that these newly discovered mediators permitted the aggressive acute inflammation stage to occur, which is so physiologically important, before then subduing the reaction and returning the body to homeostasis. But it was not yet clear whether the reduction in inflammation would also reduce pain.

Inflammation includes a number of processes, not all of which are associated with pain. For example, while systemic infections, like the flu or a cold, spur strong inflammatory reactions, they are only occasionally associated with pain. Pain only occurs when inflammatory cytokines are released near nociceptive, or damage-signaling, nerve fibers. Damaged tissues release their contents during injury or inflammation, flooding the surrounding tissues with prostaglandins (PGs) and bradykinin, which activate the secretion of histamines. Together, these chemicals make blood vessels leaky enough to permit immune cells to enter the damaged tissue from the circulation, releasing PGs creating the swelling that is a cardinal symptom of inflammation. When this process occurs in richly innervated tissues, the inflammatory mediators also cause nearby nociceptors to fire, conveying the sensation of pain.

Resolving the pain

Given that resolvins are derived from omega-3 fatty acids—that is, from essential nutritional factors—and that they are endogenous anti-inflammatory substances, it seemed a likely hypothesis that they would also have an effect on inflammation-related pain. In 2010, the lab of Ru-Rong Ji at Brigham and Women’s Hospital in Boston, in collaboration with Serhan, explored this question.[3. Z.Z. Xu et al., “Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions,” Nat Med, 16:592-97, 2010.]

Using an animal model of pain, investigators injected the paws of mice with formalin, which produces two phases of pain: an immediate reaction, relayed by the peripheral nerves; and a delayed-onset reaction, mediated by inflammation and by spinal cord neurons.3The first phase is characterized by mice licking the injected foot for about five minutes after injection. Then, after a lag of 20–30 minutes, the second phase begins with another bout of foot licking. The researchers administered two different resolvin (Rv) molecules, RvD1 and RvE1, to test their ability to reduce this pain behavior, and found both molecules to be effective when injected either into the paw or directly into the spinal canal. They noted that RvE1 diminished swelling and reduced markers of the inflammatory response, and that, compared to either morphine or COX-2 inhibitors, a much lower dose of the resolvin effectively halted pain behavior. Interestingly, only the second phase of pain behavior—mediated by spinal cord mechanisms that are often associated with chronic pain—was attenuated, indicating that RvE1 and RvD1 were likely acting via a receptor known as ChemR23, a G protein–coupled receptor found on nociceptive neurons in the dorsal root ganglia and the dorsal horn of the spinal cord. These neurons also express the transient receptor potential vanilloid 1 (TRPV1), which is the receptor for the inflammation-producing irritant found in chili pepper, capsaicin. In living mice, RvE1 was able to block the pain induced by capsaicin.

The same researchers looked at another model of inflammatory pain induced by the injection of carrageenan, which also initiates two phases of pain, but is thought to more closely mimic standard muscle pain than the formalin model. When the mice were given RvE1 or RvD1 in the hindpaw before a carrageenan injection, the pretreatment markedly reduced inflammation: the mice showed diminished swelling, fewer immune effector cells called neutrophils infiltrating the damaged tissue, and a reduced level of pro-inflammatory cytokines. Just like morphine, RvE1 did not dull the ability to sense “normal” pain. In other words, the mice did not experience numbing, but rather a more specific alleviation of the pathologic pain associated with inflammation.

Recently, researchers have begun to investigate whether chronic persistent pain might be the result of a learning response in neurons of the spine. Neurons change shape when they are actively involved in learning, both in terms of the number of physical connections between cells and the number of receptors at the synapses of those connections. Researchers have proposed that when pain persists, the neuronal connections relaying that pain strengthen, making it easier to transmit the response—thus lowering the threshold at which something feels painful.

To test whether resolvins might prevent the formation of this learned pain reaction in the spine, researchers took slices of mouse spinal cord and tested how the transmission between neurons changed in the presence and absence of resolvins. Resolvins blocked an increase in the action of tumor necrosis factor-alpha (TNF-a)—a cytokine thought to increase the frequency of synaptic transmission, and thus possibly the likelihood of forming a “pain memory”—without blocking the normal levels of transmission. Then, the authors showed that RvE1 also inhibited glutamate release—required for some types of neuronal learning—by a pathway dependent on the extracellular signal-regulated kinase (ERK). Additionally, RvE1 changed the activity of the glutamate N-methyl-D-aspartic acid receptor (NMDAR), also via the ERK pathway, supporting the concept that blocking the ERK pathway could be a promising therapeutic target for the treatment of pain.

Since the publication of the first paper by Ji and colleagues describing the analgesic effect of resolvins, others have followed. These new studies described positive effects in other pain models, and have uncovered additional mechanisms by which resolvins can diminish pain. For example, RvD1 was shown to reduce, prevent, and transiently attenuate pain associated with operation trauma in a rat model.[4. L. Huang et al., “Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1,” Pain, 152:557-65, 2011.] In this study, an oversensitivity to pain, in which a touch that is normally benign feels painful, was reduced or prevented by 20 to 40 nanograms of RvD1 injected into the spinal cord up to 2 days after the surgical trauma. However, if RvD1 was given on postoperative day 9 or 17, the reversal of pain was only transient and incomplete.

In a model of pain that mimics inflammatory arthritis in rats, RvD1 reduced an increased sensitivity to pain. The effect was partially mediated by a decrease in TNF-a and interleukin-1ß—cytokines that drive inflammation and are also thought to increase pain hypersensitivity in the central nervous system.[5. J.F. Lima-Garcia et al., “The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats,” Br J Pharmacol, 164:278-93, 2011.] In this model, systemic injection, rather than spinal administration, of the resolvins was shown to be effective, providing a much more feasible clinical application, as spinal injections themselves are associated with significant pain. Furthermore, in cell culture, RvD1 inhibited other members of the TRP family of receptors.[6. S. Bang et al., “Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception,” Br J Pharmacol, 161:707-20, 2010.] Subsequent in vivo experiments demonstrated that injecting RvD1 under the skin was sufficient to attenuate pain caused by direct activation of these TRP receptors in the mouse.

A clearer picture for the future

From the animal data summarized above, it appears that resolvins may be ideal candidates for novel analgesics. Because they are derived from lipid molecules normally produced in the body, resolvins counteract inflammation in a physiological way. Their precursors, the omega-3 fatty acids, have been tested with some success in treating pain conditions,[7. G.D. Ko, “Omega-3 fatty acids for neuropathic pain: case series,” Clin J Pain, 26:168-72, 2010.] although a recent meta-analysis did not show a definitive effect. However, resolvins appear to show effects at concentrations about 10,000 times lower than effective doses of omega-3 fatty acids—an advantage for drug development.

Intriguingly, one of the mechanisms that Ji and colleagues identified for the analgesic action of the resolvins is that they block various TRP receptors (particularly TRPV1) indirectly by blocking the TRPV1-dependent release of glutamate.3 This is particularly interesting insomuch as it may provide a better avenue for blocking TRPV. In fact, recently developed TRPV1 antagonists that have been tested in humans resulted in serious side effects such as high fever. The reason for this side effect is most likely that TRPV1 not only conveys information about pain, but also about temperature. Complete blockade of this receptor, therefore, would also block information about fever from reaching the brain, which would be unable to respond by initiating cooling mechanisms such as sweating. Since resolvins block glutamate rather than directly acting on TRPV1, they might avoid such life-threatening side effects.

Side effects of blocking TRP might be reduced even more with the use of resolvins that act specifically on certain TRP receptors, as recently demonstrated in vitro and in vivo with RvD1, which appears to be specific for TRPV3. This receptor specificity may potentially pave the way to a more tailored treatment for individual pain symptoms such as thermal or mechanical pain hypersensitivity. A further potential advantage of resolvins is that they may have a dual function as both an analgesic and an inflammatory disease-modifying drug. In fact, a number of molecules with this potential have already been investigated, including nerve growth factor and its antagonists in the treatment of nerve lesions, neuropathic pain, or osteoarthritis; erythropoietin in diabetic neuropathy; and cytokine inhibitors in rheumatoid arthritis.[8. R. Nixon et al.,“The efficacy of inhibiting tumour necrosis factor alpha and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons,” Rheumatology, 46:1140-47, 2007.] Unfortunately, of these, currently only the cytokine inhibitors have made it to clinical application.

The challenge now, as it is for every promising molecule at the preclinical stage of investigation, will be to develop resolvins into a clinically applicable form. Many of the experimental applications have been via spinal injection, which would limit the use in humans. As drugs, these molecules would need to be stable—so that they could be taken orally, for example—and long-acting. Because they act on the immune system, they might have unwanted side effects, which will need to be investigated further. In addition, although the results reported by Ji and others are impressive and reasonable, the size of the effect on pain behavior in the animals is moderate. Other analgesic drugs, which had even stronger effects than the resolvins in animal models, have failed in human clinical trials because their impact was not sufficiently different from that of placebos. The reason might be that human pain still differs significantly from even the best and most elaborate animal pain models. With all these caveats, testing resolvins in clinical trials will be the best way to determine if alleviating chronic low-grade inflammation, a factor underlying not only pathogenic pain but diseases ranging from cancer to obesity, could reduce morbidity and mortality.

Claudia Sommer is at the University of Würzburg, in Germany, and Frank Birklein is at the University Medical Center of the Johannes Gutenberg University Mainz.

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On a hypothesis that chronic pain is most often a "learned" neurological response, (a conditioned response) 2 pilot studies in 2003 utilised rapid neuro-psychological self-treatment techniques which targetted mental, mechanical, and situational triggers to spikes of chronic pain with an aim of extinguishing the conditioned responses.

The efficacy rates on 2 small groups (15 and 5) were >90% and 100% respectively, with a complete and immediate elimination of pain in >50% and >50% improvement in pain in all or the majority of the remainder.

Anecdotally, it would seem that these results are on the high side, and that although a substantial proportion of people do gain immediate and total relief, more likely is a gradual improvement over a just a few months, experiencing ups and downs with a trend to fewer flares, less intensity of flaring, reduction of medication, until cessation of all symptoms and return to normal role.

None of these results were dependent upon invasive treatments such as injection, or implantation.

As a researcher it is disappointing to see an emphasis on potentially dangerous or invasive pharmaceutical applications for chronic pain when clearly other options are available.

On a hypothesis that chronic pain is most often a "learned" neurological response, (a conditioned response) 2 pilot studies in 2003 utilised rapid neuro-psychological self-treatment techniques which targetted mental, mechanical, and situational triggers to spikes of chronic pain with an aim of extinguishing the conditioned responses.

The efficacy rates on 2 small groups (15 and 5) were >90% and 100% respectively, with a complete and immediate elimination of pain in >50% and >50% improvement in pain in all or the majority of the remainder.

Anecdotally, it would seem that these results are on the high side, and that although a substantial proportion of people do gain immediate and total relief, more likely is a gradual improvement over a just a few months, experiencing ups and downs with a trend to fewer flares, less intensity of flaring, reduction of medication, until cessation of all symptoms and return to normal role.

None of these results were dependent upon invasive treatments such as injection, or implantation.

As a researcher it is disappointing to see an emphasis on potentially dangerous or invasive pharmaceutical applications for chronic pain when clearly other options are available.

On a hypothesis that chronic pain is most often a "learned" neurological response, (a conditioned response) 2 pilot studies in 2003 utilised rapid neuro-psychological self-treatment techniques which targetted mental, mechanical, and situational triggers to spikes of chronic pain with an aim of extinguishing the conditioned responses.

The efficacy rates on 2 small groups (15 and 5) were >90% and 100% respectively, with a complete and immediate elimination of pain in >50% and >50% improvement in pain in all or the majority of the remainder.

Anecdotally, it would seem that these results are on the high side, and that although a substantial proportion of people do gain immediate and total relief, more likely is a gradual improvement over a just a few months, experiencing ups and downs with a trend to fewer flares, less intensity of flaring, reduction of medication, until cessation of all symptoms and return to normal role.

None of these results were dependent upon invasive treatments such as injection, or implantation.

As a researcher it is disappointing to see an emphasis on potentially dangerous or invasive pharmaceutical applications for chronic pain when clearly other options are available.

Did these pilot studies ever lead to a peer-reviewed publication? Â I'd be skeptical of these studies if no papers came from them after 9 years, especially with such impressive efficacy rates. Â Could you point out any references, or at least the researchers involved?

I have been in chronic pain for over twenty years and I am now seventy-three.Â I am hoping you will find something soon to give me relief as my Lortab is not working very well anymore. My Dr. says I am at the top of my allowed amount.Â I didn't understand this completely,(ha) butÂ I got the gist of it. Thank you to the researchersÂ who do this kind of work to help us.

Although there is no known "cure" there are a few things you can do that relieve chronic arthritis pain.Â One is simply grounding or earthing. Stand or sit with your bare feet touching the grass, or dirt in your garden or at a park. Concrete directly on top of dirt may work, although asphalt will usually not help as it's insulated to an extent. Do this for 10 minutes at first, and work your way up to 45 minutes. You should feel gradual pain relief, more as you go on.

Opiates only work to reduce pain for a couple of weeks, then addiction sets in with higher and higher doses. Medical marijuana taken internally is the best method to reduce pain.

You don't have to use that much cannabis to get relief. This book has great information on how to make marijuana oil and great small candies!Great e-book on medical marijuana: MARIJUANA - Guide to Buying, Growing, Harvesting, and Making Medical Marijuana Oil and Delicious Candies to Treat Pain and Ailments by Mary Bendis, Second Edition. This book has great recipes for easy marijuana oil, delicious Cannabis Chocolates, and tasty Dragon Teeth Mints! http://goo.gl/iYjPn

Opiates only work to reduce pain for a couple of weeks, then addiction sets in with higher and higher doses. Medical marijuana taken internally is the best method to reduce pain.

You don't have to use that much cannabis to get relief. This book has great information on how to make marijuana oil and great small candies!

Great e-book on medical marijuana: MARIJUANA - Guide to Buying, Growing, Harvesting, and Making Medical Marijuana Oil and Delicious Candies to Treat Pain and Ailments by Mary Bendis, Second Edition. This book has great recipes for easy marijuana oil, delicious Cannabis Chocolates, and tasty Dragon Teeth Mints! http://goo.gl/iYjPn

Although there is no known "cure" there are a few things you can do that relieve chronic arthritis pain.Â One is simply grounding or earthing. Stand or sit with your bare feet touching the grass, or dirt in your garden or at a park. Concrete directly on top of dirt may work, although asphalt will usually not help as it's insulated to an extent. Do this for 10 minutes at first, and work your way up to 45 minutes. You should feel gradual pain relief, more as you go on.

Opiates only work to reduce pain for a couple of weeks, then addiction sets in with higher and higher doses. Medical marijuana taken internally is the best method to reduce pain.

You don't have to use that much cannabis to get relief. This book has great information on how to make marijuana oil and great small candies!Great e-book on medical marijuana: MARIJUANA - Guide to Buying, Growing, Harvesting, and Making Medical Marijuana Oil and Delicious Candies to Treat Pain and Ailments by Mary Bendis, Second Edition. This book has great recipes for easy marijuana oil, delicious Cannabis Chocolates, and tasty Dragon Teeth Mints! http://goo.gl/iYjPn

Opiates only work to reduce pain for a couple of weeks, then addiction sets in with higher and higher doses. Medical marijuana taken internally is the best method to reduce pain.

You don't have to use that much cannabis to get relief. This book has great information on how to make marijuana oil and great small candies!

Great e-book on medical marijuana: MARIJUANA - Guide to Buying, Growing, Harvesting, and Making Medical Marijuana Oil and Delicious Candies to Treat Pain and Ailments by Mary Bendis, Second Edition. This book has great recipes for easy marijuana oil, delicious Cannabis Chocolates, and tasty Dragon Teeth Mints! http://goo.gl/iYjPn

Did these pilot studies ever lead to a peer-reviewed publication? Â I'd be skeptical of these studies if no papers came from them after 9 years, especially with such impressive efficacy rates. Â Could you point out any references, or at least the researchers involved?

I have been in chronic pain for over twenty years and I am now seventy-three.Â I am hoping you will find something soon to give me relief as my Lortab is not working very well anymore. My Dr. says I am at the top of my allowed amount.Â I didn't understand this completely,(ha) butÂ I got the gist of it. Thank you to the researchersÂ who do this kind of work to help us.

Did these pilot studies ever lead to a peer-reviewed publication? Â I'd be skeptical of these studies if no papers came from them after 9 years, especially with such impressive efficacy rates. Â Could you point out any references, or at least the researchers involved?

I have been in chronic pain for over twenty years and I am now seventy-three.Â I am hoping you will find something soon to give me relief as my Lortab is not working very well anymore. My Dr. says I am at the top of my allowed amount.Â I didn't understand this completely,(ha) butÂ I got the gist of it. Thank you to the researchersÂ who do this kind of work to help us.

Although there is no known "cure" there are a few things you can do that relieve chronic arthritis pain.Â One is simply grounding or earthing. Stand or sit with your bare feet touching the grass, or dirt in your garden or at a park. Concrete directly on top of dirt may work, although asphalt will usually not help as it's insulated to an extent. Do this for 10 minutes at first, and work your way up to 45 minutes. You should feel gradual pain relief, more as you go on.

Opiates only work to reduce pain for a couple of weeks, then addiction sets in with higher and higher doses. Medical marijuana taken internally is the best method to reduce pain.

You don't have to use that much cannabis to get relief. This book has great information on how to make marijuana oil and great small candies!Great e-book on medical marijuana: MARIJUANA - Guide to Buying, Growing, Harvesting, and Making Medical Marijuana Oil and Delicious Candies to Treat Pain and Ailments by Mary Bendis, Second Edition. This book has great recipes for easy marijuana oil, delicious Cannabis Chocolates, and tasty Dragon Teeth Mints! http://goo.gl/iYjPn

Opiates only work to reduce pain for a couple of weeks, then addiction sets in with higher and higher doses. Medical marijuana taken internally is the best method to reduce pain.

You don't have to use that much cannabis to get relief. This book has great information on how to make marijuana oil and great small candies!

Great e-book on medical marijuana: MARIJUANA - Guide to Buying, Growing, Harvesting, and Making Medical Marijuana Oil and Delicious Candies to Treat Pain and Ailments by Mary Bendis, Second Edition. This book has great recipes for easy marijuana oil, delicious Cannabis Chocolates, and tasty Dragon Teeth Mints! http://goo.gl/iYjPn

I was experiencing chronic pain in my legs for several years when I heard Dr. Bill Lands note that peanuts are rich in omega-6 lenoleic acid. I stopped consuming peanut butter that day and two months later the pain was gone and hasn't returned.

Eric, I'm more curious why no-one picked up on these studies. My company funded the research but we are simply not willing to pour more money in when the politics of research are so anti non-invasive or non-pharma strategies.

There's simply no money in the treatment I devised because it's easily replicated and can be taught to individuals or groups to self treat. Psychologists and physiotherapists, as part of a treatment team, would be best placed to deliver the treatment, training, and support.

In every case detailed daily records should be kept of pain locations, pain sensorimotor symptoms, pain level (especially including highest and lowest of the day), episodes of flaring whether or not in response to specific stimuli, medication taken, and ability or otherwise of performing desired role.

Over time the patient will see the downward trend and gain more confidence. Without the record keeping the patient can have a bad day and give up, not realising that there actually is a trend to resolution.

I wrote the book "The Pain Train: How to Get Off" to describe an hypothesis for chronic pain, and to detail a treatment methodology. I also have a support forum for professionals who are interested in learning and using this strategy, and it is my hope that enough people will take action that there may be a significant improvement in the way chronic pain is generally managed.

Every night as I sleep soundly in my bed, there are elderly people writhing in pain unable to sleep. The world is full of people in constant pain, who cannot get relief no matter what they try. This is unacceptable.

When your doctor implies you are at the top of your allowed amount, this merely implies you cannot take any more Lortab which is limited only by the maximum dose of Tylenol (acetaminophen), as high doses of Tylenol for extended courses can cause damage to you liver. There are MANY other drug and non-drug options beyond Lortab.

Chronic Pain can beÂ easily controlled by the use of Clinical hypnosis.Â In the 1800's English Surgeon, James Braid performed over 100 deep tissue surgeries in India using only Hypnosis.Â Hypnosis has no Ill side effects. And it also promotes Healing

Dewey, so far asÂ I am aware, the hypnosis studies were unable to be replicated. I think that there is a fairly broad view that hypnosis is not generally helpful for pain, nor for smoking cessation. Anecdotally, everyone knows someone who's been helped, but when you look at meta analyses you see that the percentage is often less than 1% of a given treatment population.

Plus chronic pain is neurophysiologically different from acute pain. I think most treatment teams recognise that two very different approaches are required to two very different beasts.

When your doctor implies you are at the top of your allowed amount, this merely implies you cannot take any more Lortab which is limited only by the maximum dose of Tylenol (acetaminophen), as high doses of Tylenol for extended courses can cause damage to you liver. There are MANY other drug and non-drug options beyond Lortab.

Chronic Pain can beÂ easily controlled by the use of Clinical hypnosis.Â In the 1800's English Surgeon, James Braid performed over 100 deep tissue surgeries in India using only Hypnosis.Â Hypnosis has no Ill side effects. And it also promotes Healing

Dewey, so far asÂ I am aware, the hypnosis studies were unable to be replicated. I think that there is a fairly broad view that hypnosis is not generally helpful for pain, nor for smoking cessation. Anecdotally, everyone knows someone who's been helped, but when you look at meta analyses you see that the percentage is often less than 1% of a given treatment population.

Plus chronic pain is neurophysiologically different from acute pain. I think most treatment teams recognise that two very different approaches are required to two very different beasts.

I was experiencing chronic pain in my legs for several years when I heard Dr. Bill Lands note that peanuts are rich in omega-6 lenoleic acid. I stopped consuming peanut butter that day and two months later the pain was gone and hasn't returned.

Eric, I'm more curious why no-one picked up on these studies. My company funded the research but we are simply not willing to pour more money in when the politics of research are so anti non-invasive or non-pharma strategies.

There's simply no money in the treatment I devised because it's easily replicated and can be taught to individuals or groups to self treat. Psychologists and physiotherapists, as part of a treatment team, would be best placed to deliver the treatment, training, and support.

In every case detailed daily records should be kept of pain locations, pain sensorimotor symptoms, pain level (especially including highest and lowest of the day), episodes of flaring whether or not in response to specific stimuli, medication taken, and ability or otherwise of performing desired role.

Over time the patient will see the downward trend and gain more confidence. Without the record keeping the patient can have a bad day and give up, not realising that there actually is a trend to resolution.

I wrote the book "The Pain Train: How to Get Off" to describe an hypothesis for chronic pain, and to detail a treatment methodology. I also have a support forum for professionals who are interested in learning and using this strategy, and it is my hope that enough people will take action that there may be a significant improvement in the way chronic pain is generally managed.

Every night as I sleep soundly in my bed, there are elderly people writhing in pain unable to sleep. The world is full of people in constant pain, who cannot get relief no matter what they try. This is unacceptable.

I was experiencing chronic pain in my legs for several years when I heard Dr. Bill Lands note that peanuts are rich in omega-6 lenoleic acid. I stopped consuming peanut butter that day and two months later the pain was gone and hasn't returned.

Eric, I'm more curious why no-one picked up on these studies. My company funded the research but we are simply not willing to pour more money in when the politics of research are so anti non-invasive or non-pharma strategies.

There's simply no money in the treatment I devised because it's easily replicated and can be taught to individuals or groups to self treat. Psychologists and physiotherapists, as part of a treatment team, would be best placed to deliver the treatment, training, and support.

In every case detailed daily records should be kept of pain locations, pain sensorimotor symptoms, pain level (especially including highest and lowest of the day), episodes of flaring whether or not in response to specific stimuli, medication taken, and ability or otherwise of performing desired role.

Over time the patient will see the downward trend and gain more confidence. Without the record keeping the patient can have a bad day and give up, not realising that there actually is a trend to resolution.

I wrote the book "The Pain Train: How to Get Off" to describe an hypothesis for chronic pain, and to detail a treatment methodology. I also have a support forum for professionals who are interested in learning and using this strategy, and it is my hope that enough people will take action that there may be a significant improvement in the way chronic pain is generally managed.

Every night as I sleep soundly in my bed, there are elderly people writhing in pain unable to sleep. The world is full of people in constant pain, who cannot get relief no matter what they try. This is unacceptable.

When your doctor implies you are at the top of your allowed amount, this merely implies you cannot take any more Lortab which is limited only by the maximum dose of Tylenol (acetaminophen), as high doses of Tylenol for extended courses can cause damage to you liver. There are MANY other drug and non-drug options beyond Lortab.

Chronic Pain can beÂ easily controlled by the use of Clinical hypnosis.Â In the 1800's English Surgeon, James Braid performed over 100 deep tissue surgeries in India using only Hypnosis.Â Hypnosis has no Ill side effects. And it also promotes Healing

Dewey, so far asÂ I am aware, the hypnosis studies were unable to be replicated. I think that there is a fairly broad view that hypnosis is not generally helpful for pain, nor for smoking cessation. Anecdotally, everyone knows someone who's been helped, but when you look at meta analyses you see that the percentage is often less than 1% of a given treatment population.

Plus chronic pain is neurophysiologically different from acute pain. I think most treatment teams recognise that two very different approaches are required to two very different beasts.

I have had chronic myofascial pain and neuropathic pain for six years. I took anti-seizure drugs to help with the pain in the nerves and had weekly trigger point injections for years. In addition, I was taking Tylenol 3s, and Celebrex to try to control the pain. Nothing has worked as well as Lyrica. Now, instead of 2,800 mg of Neurontin, I take 225 mg of Lyrica. I have dropped the Celebrex and take Tylenol 3s rarely! Lyrica has changed my life, and after six years, I am finally ready to get back to work and livingLeonard Winstonwww.pharmaspider.com

I have had chronic myofascial pain and neuropathic pain for six years. I took anti-seizure drugs to help with the pain in the nerves and had weekly trigger point injections for years. In addition, I was taking Tylenol 3s, and Celebrex to try to control the pain. Nothing has worked as well as Lyrica. Now, instead of 2,800 mg of Neurontin, I take 225 mg of Lyrica. I have dropped the Celebrex and take Tylenol 3s rarely! Lyrica has changed my life, and after six years, I am finally ready to get back to work and livingLeonard Winstonwww.pharmaspider.com

I have had chronic myofascial pain and neuropathic pain for six years. I took anti-seizure drugs to help with the pain in the nerves and had weekly trigger point injections for years. In addition, I was taking Tylenol 3s, and Celebrex to try to control the pain. Nothing has worked as well as Lyrica. Now, instead of 2,800 mg of Neurontin, I take 225 mg of Lyrica. I have dropped the Celebrex and take Tylenol 3s rarely! Lyrica has changed my life, and after six years, I am finally ready to get back to work and livingLeonard Winstonwww.pharmaspider.com

The studies and results are impressive. But the major question is, if all this is true, why subjects who take regularly EPA/DHA do not have less pain, when EPA/DHA is given pain is not relieved, and why EPA/DHA is not suitable as pain relievers. Obviously, something more need to be learned and we are missing some thing. What is good in animal studies may not be good for humans? Â U N Das

The studies and results are impressive. But the major question is, if all this is true, why subjects who take regularly EPA/DHA do not have less pain, when EPA/DHA is given pain is not relieved, and why EPA/DHA is not suitable as pain relievers. Obviously, something more need to be learned and we are missing some thing. What is good in animal studies may not be good for humans? Â U N Das

The studies and results are impressive. But the major question is, if all this is true, why subjects who take regularly EPA/DHA do not have less pain, when EPA/DHA is given pain is not relieved, and why EPA/DHA is not suitable as pain relievers. Obviously, something more need to be learned and we are missing some thing. What is good in animal studies may not be good for humans? Â U N Das

In the 1960s, I think it was, there was a lot of hype, or data as the case may be, in reference to hypnotherapy in conjunction with "rolfing."Â Actually rolfing became established in the 1920s and is generally asserted as having no "scientific" evidence to support it.Â The addition of hypnotherapy to the rolfing massage techniques was instrumental (it was claimed) in evidencing subconscious emotional factors in the etiology of chronic pain of the kind addressed in this article.

This is not intended to question anything nor to defend anything.Â I simply find it interesting that the subject of hypnotherapy arose in connection this research.Â Also,I cannot help but be curious about old-near-forgotten remedies that might justify a little application of more current knowledge, just in case there might now be tests more capable of ruling in, and not only out, a kind of treatment that has been disparaged.

The entire subject of chronic residual pain, counter-productive in either a physiological or psychological sense, is at romantic subject -- especially for those who are its victims.

In the 1960s, I think it was, there was a lot of hype, or data as the case may be, in reference to hypnotherapy in conjunction with "rolfing."Â Actually rolfing became established in the 1920s and is generally asserted as having no "scientific" evidence to support it.Â The addition of hypnotherapy to the rolfing massage techniques was instrumental (it was claimed) in evidencing subconscious emotional factors in the etiology of chronic pain of the kind addressed in this article.

This is not intended to question anything nor to defend anything.Â I simply find it interesting that the subject of hypnotherapy arose in connection this research.Â Also,I cannot help but be curious about old-near-forgotten remedies that might justify a little application of more current knowledge, just in case there might now be tests more capable of ruling in, and not only out, a kind of treatment that has been disparaged.

The entire subject of chronic residual pain, counter-productive in either a physiological or psychological sense, is at romantic subject -- especially for those who are its victims.

In the 1960s, I think it was, there was a lot of hype, or data as the case may be, in reference to hypnotherapy in conjunction with "rolfing."Â Actually rolfing became established in the 1920s and is generally asserted as having no "scientific" evidence to support it.Â The addition of hypnotherapy to the rolfing massage techniques was instrumental (it was claimed) in evidencing subconscious emotional factors in the etiology of chronic pain of the kind addressed in this article.

This is not intended to question anything nor to defend anything.Â I simply find it interesting that the subject of hypnotherapy arose in connection this research.Â Also,I cannot help but be curious about old-near-forgotten remedies that might justify a little application of more current knowledge, just in case there might now be tests more capable of ruling in, and not only out, a kind of treatment that has been disparaged.

The entire subject of chronic residual pain, counter-productive in either a physiological or psychological sense, is at romantic subject -- especially for those who are its victims.

Further research, along the lines suggested in this article, will want to take into account any adverse impact upon "needed" inflammation.Â As is acknowledged early in the article, inflammation is one of the body's physiological tools for dealing with various kinds of trauma etiologies.Â Surely, in treating or preventing a chronic "learned" pain situation, we would not wish concomitantly to prevent beneficial inflammations.

Further research, along the lines suggested in this article, will want to take into account any adverse impact upon "needed" inflammation.Â As is acknowledged early in the article, inflammation is one of the body's physiological tools for dealing with various kinds of trauma etiologies.Â Surely, in treating or preventing a chronic "learned" pain situation, we would not wish concomitantly to prevent beneficial inflammations.

Further research, along the lines suggested in this article, will want to take into account any adverse impact upon "needed" inflammation.Â As is acknowledged early in the article, inflammation is one of the body's physiological tools for dealing with various kinds of trauma etiologies.Â Surely, in treating or preventing a chronic "learned" pain situation, we would not wish concomitantly to prevent beneficial inflammations.

Numerous studies by multiple independent laboratories have shown that the underpinnings of chronic pain are not simply 'in the patient's head' as a learned response. The only exception to the 'all in the head' approach of chronic pain might be phantom limb pain, as V.S. Ramachandran's work with mirror therapy is very promising. However, phantom limb pain is thought to be more of a 'mis-feed' of visual, spatial and proprioceptive input, rather than a learned response. Once this is reconciled, pain subsides. Phantom limb pain isn't what you are describing here, so until your findings are published and found to be repeatable, I am sure you can understand a certain amount of raised eyebrows.

Â Furthermore, for these pilot studies to be devoid of possible bias, these patients would have had to have been blinded as to the notion that any sort of pain manipulation would be occurring. This would mean that recruitment into this study would have to be conducted along side healthy, non-chronic pain patients, and would probably have been beyond a pilot study. Otherwise, how can you discount the potential for a very real and pervasive placebo effect (now believed to hinge on opioid and cannabinoid receptors) leading to descending pain control?Â

Neuropathy is specifically whereby injury to a nerve terminal in the CNS, or the length of the nerve in the PNS, results in chronic pain. In some cases, like diabetes, the injury is sustained, or in MS, pain persists even when the lesion has healed. The notion within the pain field is that this nerve injury 'revs up' the spinal cord, as noted in this article, and chronic pain is generally associated along the nerve tract, as a result, (i.e. - the symptoms of sciatica are associated with inflammation/injury of the common sciatic nerve). Complex regional pain, however, is a different beast. The actual underpinnings of this disease state is poorly understood, as the pain felt by the patient does not hold a consistent pattern. Lets say you stepped on a tack with your left foot, and you got a small wound that, yes, hurt for a few weeks. After a few weeks of this, then you developed pain in your right knee, and then in your left elbow. This pattern of pain then lasts for more than 3 months, shifting from the knee to your right leg and back to your knee, and from your left elbow to your left wrist. That is essentially an example of complex regional pain. Given that that prick to your left foot would induce some inflammation to your common sciatic and saphenous nerves, at best, this neuronal approach does not account for the spread of pain up to higher portions of the body. Your upper body nerves are not injured, and thus, complex regional pain syndrome is not explained in this article as a neuropathy. This means that the spread of the pain symptoms are due to changes within the central nervous system itself, and why taking simple NSAIDS are often not enough for chronic pain relief, and why targeting the central nervous system for enduring pain relief is attractive.Â

Neuropathy is specifically whereby injury to a nerve terminal in the CNS, or the length of the nerve in the PNS, results in chronic pain. In some cases, like diabetes, the injury is sustained, or in MS, pain persists even when the lesion has healed. The notion within the pain field is that this nerve injury 'revs up' the spinal cord, as noted in this article, and chronic pain is generally associated along the nerve tract, as a result, (i.e. - the symptoms of sciatica are associated with inflammation/injury of the common sciatic nerve). Complex regional pain, however, is a different beast. The actual underpinnings of this disease state is poorly understood, as the pain felt by the patient does not hold a consistent pattern. Lets say you stepped on a tack with your left foot, and you got a small wound that, yes, hurt for a few weeks. After a few weeks of this, then you developed pain in your right knee, and then in your left elbow. This pattern of pain then lasts for more than 3 months, shifting from the knee to your right leg and back to your knee, and from your left elbow to your left wrist. That is essentially an example of complex regional pain. Given that that prick to your left foot would induce some inflammation to your common sciatic and saphenous nerves, at best, this neuronal approach does not account for the spread of pain up to higher portions of the body. Your upper body nerves are not injured, and thus, complex regional pain syndrome is not explained in this article as a neuropathy. This means that the spread of the pain symptoms are due to changes within the central nervous system itself, and why taking simple NSAIDS are often not enough for chronic pain relief, and why targeting the central nervous system for enduring pain relief is attractive.Â

Numerous studies by multiple independent laboratories have shown that the underpinnings of chronic pain are not simply 'in the patient's head' as a learned response. The only exception to the 'all in the head' approach of chronic pain might be phantom limb pain, as V.S. Ramachandran's work with mirror therapy is very promising. However, phantom limb pain is thought to be more of a 'mis-feed' of visual, spatial and proprioceptive input, rather than a learned response. Once this is reconciled, pain subsides. Phantom limb pain isn't what you are describing here, so until your findings are published and found to be repeatable, I am sure you can understand a certain amount of raised eyebrows.

Â Furthermore, for these pilot studies to be devoid of possible bias, these patients would have had to have been blinded as to the notion that any sort of pain manipulation would be occurring. This would mean that recruitment into this study would have to be conducted along side healthy, non-chronic pain patients, and would probably have been beyond a pilot study. Otherwise, how can you discount the potential for a very real and pervasive placebo effect (now believed to hinge on opioid and cannabinoid receptors) leading to descending pain control?Â

Numerous studies by multiple independent laboratories have shown that the underpinnings of chronic pain are not simply 'in the patient's head' as a learned response. The only exception to the 'all in the head' approach of chronic pain might be phantom limb pain, as V.S. Ramachandran's work with mirror therapy is very promising. However, phantom limb pain is thought to be more of a 'mis-feed' of visual, spatial and proprioceptive input, rather than a learned response. Once this is reconciled, pain subsides. Phantom limb pain isn't what you are describing here, so until your findings are published and found to be repeatable, I am sure you can understand a certain amount of raised eyebrows.

Â Furthermore, for these pilot studies to be devoid of possible bias, these patients would have had to have been blinded as to the notion that any sort of pain manipulation would be occurring. This would mean that recruitment into this study would have to be conducted along side healthy, non-chronic pain patients, and would probably have been beyond a pilot study. Otherwise, how can you discount the potential for a very real and pervasive placebo effect (now believed to hinge on opioid and cannabinoid receptors) leading to descending pain control?Â

Neuropathy is specifically whereby injury to a nerve terminal in the CNS, or the length of the nerve in the PNS, results in chronic pain. In some cases, like diabetes, the injury is sustained, or in MS, pain persists even when the lesion has healed. The notion within the pain field is that this nerve injury 'revs up' the spinal cord, as noted in this article, and chronic pain is generally associated along the nerve tract, as a result, (i.e. - the symptoms of sciatica are associated with inflammation/injury of the common sciatic nerve). Complex regional pain, however, is a different beast. The actual underpinnings of this disease state is poorly understood, as the pain felt by the patient does not hold a consistent pattern. Lets say you stepped on a tack with your left foot, and you got a small wound that, yes, hurt for a few weeks. After a few weeks of this, then you developed pain in your right knee, and then in your left elbow. This pattern of pain then lasts for more than 3 months, shifting from the knee to your right leg and back to your knee, and from your left elbow to your left wrist. That is essentially an example of complex regional pain. Given that that prick to your left foot would induce some inflammation to your common sciatic and saphenous nerves, at best, this neuronal approach does not account for the spread of pain up to higher portions of the body. Your upper body nerves are not injured, and thus, complex regional pain syndrome is not explained in this article as a neuropathy. This means that the spread of the pain symptoms are due to changes within the central nervous system itself, and why taking simple NSAIDS are often not enough for chronic pain relief, and why targeting the central nervous system for enduring pain relief is attractive.Â

Since 80% of health care cost are caused by lifestyle choices one could change how one lives. Or like the lawyer in movie "lair lair" says to a criminal getting caught all the the time and in need of professional help one could just "stop breaking the law." As someone who has designed and repairÂ electronics I haveÂ mentioned to customer that the warrenty is void if you abuse it. The Dentist always said brush them or loose them.Â A Doctor once told me, after rupturing my spleen,Â don't play football any more or it might KILL YOU! Plain enough.

Since 80% of health care cost are caused by lifestyle choices one could change how one lives. Or like the lawyer in movie "lair lair" says to a criminal getting caught all the the time and in need of professional help one could just "stop breaking the law." As someone who has designed and repairÂ electronics I haveÂ mentioned to customer that the warrenty is void if you abuse it. The Dentist always said brush them or loose them.Â A Doctor once told me, after rupturing my spleen,Â don't play football any more or it might KILL YOU! Plain enough.

Since 80% of health care cost are caused by lifestyle choices one could change how one lives. Or like the lawyer in movie "lair lair" says to a criminal getting caught all the the time and in need of professional help one could just "stop breaking the law." As someone who has designed and repairÂ electronics I haveÂ mentioned to customer that the warrenty is void if you abuse it. The Dentist always said brush them or loose them.Â A Doctor once told me, after rupturing my spleen,Â don't play football any more or it might KILL YOU! Plain enough.

I also suffer from chronic pain (two types of arthritis) but I have learned to tune it out. I am at the point where I don't even need pain control after operations any more. Â I use exercise as my drug of choice.

I also suffer from chronic pain (two types of arthritis) but I have learned to tune it out. I am at the point where I don't even need pain control after operations any more. Â I use exercise as my drug of choice.

I also suffer from chronic pain (two types of arthritis) but I have learned to tune it out. I am at the point where I don't even need pain control after operations any more. Â I use exercise as my drug of choice.

My background is a Ph.D. in clinical psychology with this said,Â is to le t you know that Â I don't have a science Â background to understand some formula or concepts explain hereÂ but I keep reading to see ifÂ Â there is an explanation of the pain that I feel inÂ allÂ the muscle of my body.Â If you press just oneÂ finger, to any part of my body it hurts like if a nail has being inserted.Â You have no idea of howÂ i live each day.Â I don't haveÂ any one to complain to feel sorry for me or secondary gains, in financial or emotional means.Â It isÂ said that is related to stress and IÂ think it could be because I worked for more than 25 yearsÂ as a psychologist for a very sick polulation that kept meÂ in my toes.Â Any way, I am just hoping to find solution for it that is not related to medications that in the long term will harm my internal organs.Â The fashionable word for this is fybromyalgia.Â Â

My background is a Ph.D. in clinical psychology with this said,Â is to le t you know that Â I don't have a science Â background to understand some formula or concepts explain hereÂ but I keep reading to see ifÂ Â there is an explanation of the pain that I feel inÂ allÂ the muscle of my body.Â If you press just oneÂ finger, to any part of my body it hurts like if a nail has being inserted.Â You have no idea of howÂ i live each day.Â I don't haveÂ any one to complain to feel sorry for me or secondary gains, in financial or emotional means.Â It isÂ said that is related to stress and IÂ think it could be because I worked for more than 25 yearsÂ as a psychologist for a very sick polulation that kept meÂ in my toes.Â Any way, I am just hoping to find solution for it that is not related to medications that in the long term will harm my internal organs.Â The fashionable word for this is fybromyalgia.Â Â

My background is a Ph.D. in clinical psychology with this said,Â is to le t you know that Â I don't have a science Â background to understand some formula or concepts explain hereÂ but I keep reading to see ifÂ Â there is an explanation of the pain that I feel inÂ allÂ the muscle of my body.Â If you press just oneÂ finger, to any part of my body it hurts like if a nail has being inserted.Â You have no idea of howÂ i live each day.Â I don't haveÂ any one to complain to feel sorry for me or secondary gains, in financial or emotional means.Â It isÂ said that is related to stress and IÂ think it could be because I worked for more than 25 yearsÂ as a psychologist for a very sick polulation that kept meÂ in my toes.Â Any way, I am just hoping to find solution for it that is not related to medications that in the long term will harm my internal organs.Â The fashionable word for this is fybromyalgia.Â Â

With regrets for not being able to cite the specific reference, I recall reading within the past month or so a peer reviewed study in which neuropathologies were treated with a regimine of an over-the-counter NSAID in combination with omega three,

Perhaps some kind reader or editor of this journal will provide us a specific reference.

According to that study, as I recall, this treatment regimine resulted in a substantial long-term recessing in inflammation and pain, although not total remission of symptoms.